Nomenclature

• Currently preferred name is HSS/DRESS - hypersensitivity syndrome/drug rash, eosinophilia, systemic symptoms
• Historical synonyms used in the literature include:
  • AHS - anticonvulsant hypersensitivity syndrome
  • DiHS - drug-induced hypersensitivity syndrome
  • HSS - hypersensitivity syndrome
  • DIDMOHS - drug-induced delayed multi-organ hypersensitivity syndrome

Diagnosis

• Dignostic criteria are not well-defined due to variability in presentation
• Clinical diagnosis
  • Key features may include:
    

    

    • Reaction starting 2-8 (maybe 10) weeks after drug started
      • 2 weeks usually in case of antiepileptic agents, for other drugs onset may be 4-21 days after first dose
    • Fever
    • Variable rashes (>70%) - urticated maculopapular eruption most common, but vesicles, bullae, pustules, cheilitis, purpura (especially on lower legs), target lesions and erythroderma have been described
    • Facial edema - sometimes gross and mistaken for angioedema
    • Hematologic abnormalities: eosinophilia (occurs in >50%, often >1 G/L), leukocytosis
    • Involvement of at least one internal organ
      • Liver (in >80% of cases), which can progress to failure
      • Kidney, muscle, lung, heart, pancreas
    • Lymphadenopathy
    • Mucosal involvement infrequent
  • Other features may include atypical lymphocytosis, HHV6 reactivation, other organ involvement (renal, cardiac, pulmonary)
  • Symptoms may worsen or become recurrent after drug discontinued and last weeks-months despite discontinuation
    • May be related to reactivation of HHV-6, EBV, or CMV
  • DRESS may induce a transient state of intolerance to other drugs (such as acetaminophen) during the acute phase, which may persist for as long as activated lymphocytes are detectable in the circulation, and occasionally this intolerance may become persistent
  • HSS/DRESS is part of a disease spectrum, from mild ("mini-DRESS") to full-blown disease with life-threatening organ dysfunction

• Bocquet’s criteria require meeting the following 3 features:
  • Skin eruption
  • Blood eosinophilia (>1.5×103/μL) or the presence of atypical lymphocytes
  • Internal organ involvement, including lymphadenopathies (>2 cm in diameter), hepatitis (liver transaminases values > twice the upper normal limit), interstitial nephritis, and interstitial pneumonia or carditis)

DRESS Time Course

DRESS Diagnosis Score

Triggers

• Anticonvulsants, allopurinol, minocycline, sulfasalazine and abacavir are most commonly associated drugs
• Other reported drugs include: sulfonamides, allopurinol, dapsone, nevirapine, hydroxychloroquine, NSAIDs, cyclosporine, HCTZ, vancomycin, celecoxib, vancomycin
  • Not associated with gabapentin or valproic acid.
• HHV6 infection or reactivation has been detected within 2-3 weeks of symptom onset and may be an indicator of more severe disease

DRESS-HLA-Drug Associations

Anticonvulsant Hypersensitivity Syndrome vs. DRESS

• Anticonvulsant hypersensitivity syndrome is mainly associated with aromatic anticonvulsant drugs and is related to an inherited deficiency of epoxide hydrolase
• Phenytoin, carbamazepine, and phenobarbital are considered cross-reactive, but valproic acid, gabapentin, and lamotrigine are therapeutic alternatives.
• Slower in onset than DRESS and presents with skin nodules, plaques, and lymphadenopathy at times confused with lymphoreticular malignant tumors (pseudolymphoma)

Treatment

• Discontinue drug, but symptoms may worsen after discontinuation and last weeks-months despite discontinuation
• Moderate-high dose oral corticosteroids, but response may be suboptimal and can result in a prolonged exposure to systemic steroids
• Other immunosuppressants (e.g. cyclosporine) are sometimes required
• Case reports of IVIG suggest that it is helpful, possibly by clearing viremia

References